Apolipoprotein-E (apo-E) accumulates in plasma of all animal species which develop hypercholesterolemia and atherosclerosis in response to cholesterol feeding; it also accumulates and appears to have an abnormal isopeptide distribution (increased E3/E2) in human subjects with type III hyperlipoproteinemia. The proposed studies will investigate the diagnostic utility of the E3/E2 ratio, its potential as a genetic marker, the genetic transmission of type III in families of patients with this disorder, and the potential role of partial E3 deficiency in forms of hyperlipidemia other than type III. Other studies will involve development and validation of a technique for the measurement of apo-E turnover and comparative studies of apo-E, apo-B, and cholesterol turnover in subjects (including those with type III) characterized by lipoprotein distributions. Finally, paired studies of such subjects before and during metabolic perturbations will investigate the mechanism of changes in lipoprotein lipid levels induced by cholesterol feeding, high carbohydrate (low fat), hypercaloric and hypocaloric, and alcohol-containing diets or treatment with estrogen, androgen (oxandrolone), thyroid hormone or clofibrate.